Cymévan may be available in the countries listed below.
Ganciclovir sodium salt (a derivative of Ganciclovir) is reported as an ingredient of Cymévan in the following countries:
International Drug Name Search
Tildiem LA 200mg Prolonged-Release Capsules
Each capsule contains a combination of immediate-release and coated prolonged-release pellets with 200mg diltiazem hydrochloride as the active ingredient.
For a full list of excipients, see Section 6.1
Prolonged-release capsule
Opaque capsules with a grey body and pink cap, containing white to off-white pellets.
Mild to moderate hypertension and angina pectoris.
Tildiem LA 200 is a prolonged release product for once daily dosing. The capsules should not be chewed but swallowed whole with water, ideally before or during a meal. The dosage requirements may differ in patients with angina or hypertension.
Tildiem (diltiazem hydrochloride) is available in a range of presentations to enable dosage to be adjusted to meet the individual requirements of the patient. Careful titration of the dose should be considered where appropriate, as individual patient response may vary. When changing from one type of Tildiem formulation to another it may be necessary to adjust the dosage until a satisfactory response is obtained. To ensure consistency of response once established, particularly in the prolonged release formulations, Tildiem LA 200 should continue to be prescribed by brand name.
Adults:
Angina and hypertension: The usual starting dose is Tildiem LA 200 once daily. This dose may be increased to Tildiem LA 300 once daily, or 2 capsules of Tildiem LA 200 daily (400 mg), and if clinically indicated a higher dose of one Tildiem LA 300 plus one Tildiem LA 200 capsule (total 500 mg) may be considered.
Elderly and patients with impaired hepatic or renal function:
Heart rate should be monitored and if it falls below 50 beats per minute the dose should not be increased. Plasma levels of diltiazem can be increased in this group of patients.
Angina and hypertension: the initial dose should be one Tildiem LA 200 capsule daily. This dose may be increased to one capsule of Tildiem LA 300 daily if clinically indicated.
Children:
Safety and efficacy in children have not been established. Therefore diltiazem is not recommended for use in children.
Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker.
Severe bradycardia (less than 50 beats per minute).
Left ventricular failure with pulmonary stasis.
Lactation.
Concurrent use with dantrolene infusion (see section 4.5 Interactions with other medicinal products and other forms of interaction).
Hypersensitivity to diltiazem or to any of the excipients
Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a 1st degree AV block or prolonged PR interval detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).
Increase of plasma concentrations of diltiazem may be observed in the elderly and patients with renal or hepatic insufficiency. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.
In the case of general anaesthesia, the anaesthetist must be informed that the patient is taking diltiazem. The depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.
Treatment with diltiazem may be associated with mood changes, including depression. Early recognition of relevant symptoms is important, especially in predisposed patients. In such cases, drug discontinuation should be considered.
Diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk of developing an intestinal obstruction.
Combination Contraindicated For Safety Reasons:
Dantrolene (infusion)
Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and dantrolene are administered concomitantly.
The combination of a calcium antagonist and dantrolene is therefore potentially dangerous (see section 4.3 Contraindications).
Combinations Requiring Caution:
Alpha-antagonists
Increased anti-hypertensive effects. Concomitant treatment with alpha-antagonists may produce or aggravate hypotension. The combination of diltiazem with an alpha antagonist should be considered only with strict monitoring of blood pressure.
Beta-blockers
Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect).
Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.
Amiodarone, Digoxin
Increased risk of bradycardia; caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.
Antiarrhythmic agents
Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended due to the risk of increased cardiac adverse effects due to an additive effect. This combination should only be used under close clinical and ECG monitoring.
Nitrate derivatives:
Increased hypotensive effects and faintness (additive vasodilating effects).
In all patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.
Ciclosporin
Increase in circulating ciclosporin levels. It is recommended that the ciclosporin dose be reduced, renal function be monitored, circulating ciclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation.
Carbamazepine
Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
Theophylline
Increase in circulating theophylline levels.
Anti-H2 agents (cimetidine and ranitidine)
Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H2 agents. An adjustment in diltiazem daily dose may be necessary.
Rifampicin
Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.
Lithium
Risk of increase in lithium-induced neurotoxicity.
Combinations To Be Taken Into Account:
Diltiazem is metabolised by CYP3A4. A moderate (less than 2-fold) increase of diltiazem plasma concentration in cases of co-administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other CYP3A4 substrates may result in an increase in plasma concentration of either co-administered drug. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
Statins:
Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins. The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with statins metabolised by CYP3A4 (e.g. atorvastatin, fluvastatin, and simvastatin). An adjustment of the dose of statin may be necessary (see also product information of the relevant statin). When possible, it is recommended to use a statin not metabolised by CYP3A4 (e.g. pravastatin) with diltiazem.
Benzodiazepines (midazolam, triazolam)
Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing short-acting benzodiazepines matabolised by the CYP3A4 pathway in patients using diltiazem.
Corticosteroids (methylprednisolone):
Diltiazem can increase methylprednisolone levels (through inhibition of CYP3A4 and possible inhibition of P-glycoprotein). The patient should be monitored when initiating methylprednisolone treatment. An adjustment to the dose of methylprednisolone may be necessary.
General Information To Be Taken Into Account:
Due to the potential for additive effects, caution and careful titration are necessary in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction.
Pregnancy: There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity (see section 5.3) in certain animal species (rat, mice, rabbit). Diltiazem is therefore not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.
Breast feeding: as this drug is excreted in breast milk, breast feeding whilst taking diltiazem is contraindicated.
On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise (common), the ability to drive and use machines could be altered. However, no studies have been performed.
The following CIOMS frequency rating is used, when applicable: Very common (
Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
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The clinical effects of acute overdose can involve pronounced hypotension leading to collapse, sinus bradycardia with or without isorhythmic dissociation, and atrioventricular conduction disturbances.
Treatment, under hospital supervision, will include gastric lavage, osmotic diuresis. Conduction disturbances may be managed by temporary cardiac pacing.
Proposed corrective treatments: atropine, vasopressors, inotropic agents, glucagon and calcium gluconate infusion.
Pharmacotherapeutic group: Calcium channel blockers; Benzothiazepine derivatives, ATC code: C08DB01
Calcium antagonist, antihypertensive agent.
Diltiazem restricts calcium entry into the slow calcium channel of vascular smooth muscle and myocardial muscle fibres in a voltage-dependent manner. By this mechanism, diltiazem reduces the concentration of intracellular calcium in contractile protein.
In animals: diltiazem increases coronary blood flow without inducing any coronary steal phenomena. It acts both on small, large and collateral arteries. This vasodilator effect, which is moderate on peripheral systemic arterial territories, can be seen at doses that are not negatively inotropic.
The two major active circulating metabolites, i.e. desacetyl diltiazem and N-monodesmethyl diltiazem, possess pharmacological activity in angina corresponding to 10 and 20% respectively of that of the parent compound.
In humans: diltiazem increases coronary blood flow by reducing coronary resistance.
Due to its moderate bradycardia-inducing activity and the reduction in systemic arterial resistance, diltiazem reduces cardiac workload.
Tildiem LA does not have a significant myocardial depressant action in man.
Diltiazem is well absorbed (90%) in healthy volunteers following oral administration.
The prolonged release capsule provides prolonged absorption of the active constituent, producing steady state plasma concentrations between 2 and 14 hours post-dose, during which time peak plasma levels occur.
Bioavailability of Tildiem LA relative to the Tildiem 60mg formulation is approximately 80%. The mean apparent plasma half-life is 8 hours.
Diltiazem in plasma is 80 to 85% protein bound and is poorly dialysed. It is extensively metabolised by the liver.
The major circulating metabolite, N-monodesmethyl diltiazem accounts for approximately 35% of the circulating diltiazem.
Less than 5% of diltiazem is excreted unchanged in the urine.
Twenty four hours after intake, plasma concentrations remain, even after the 200 mg dose administration, at the level of 50 ng/ml, in patients. During long term administration in any one patient, plasma concentrations of diltiazem remained constant.
Mean plasma concentrations in the elderly and patients with renal and hepatic insufficiency are higher than in young subjects.
Food intake does not significantly affect the kinetics of Tildiem LA, however, when administered with food, absorption was observed to be higher in the first few hours post-dose.
Diltiazem and its metabolites are poorly dialysed.
Once daily formulations of diltiazem have been shown to have different pharmacokinetic profiles and therefore it is not advised to substitute different brands for one another.
Pregnancy: Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg q.d. or 8 mg/kg q.d. for a 60-kg patient) resulted in embryo and fetal lethality. These studies revealed, in one species or another, a propensity to cause fetal abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights, pup survival, as well as prolonged delivery times and an increased incidence of stillbirths.
Microcrystalline cellulose
Acrylic and methacrylic esters co-polymer
Ethylcellulose, sodium carboxymethylcellulose
Diacetylated monoglycerides
Magnesium stearate.
In the capsule:
Gelatin
Black iron oxide (E172)
Titanium dioxide (E171)
Red iron oxide (E172).
Not applicable
3 years
Store below 25 C.
28 capsules, in a PVC/foil blister strip.
No special requirements
Sanofi-aventis
One Onslow Street
Guildford
Surrey, GU1 4YS, UK
PL 04425/0639
Date of first authorisation: 17 February 1995
Date of latest renewal: 23 September 2005
13 April 2011
POM
Dersa may be available in the countries listed below.
Sulfadiazine silver (a derivative of Sulfadiazine) is reported as an ingredient of Dersa in the following countries:
International Drug Name Search
Generic Name: acetaminophen (oral) (a SEET a MIN oh fen)
Brand Names: Acetaminophen Quickmelt, Actamin, Adprin B, Anacin AF, Apra, Bromo Seltzer, Children's Tylenol, Children's Tylenol Meltaway, Ed-APAP, Elixsure Fever/Pain, Genebs, Infants Tylenol Concentrated Drops, Leader 8 Hour Pain Reliever, Little Fevers, Little Fevers Children's Fever/Pain Reliever, Mapap, Mapap Arthritis Pain, Mapap Extra Strength Rapid Burst, Mapap Infant Drops, Mapap Infants', Mapap Meltaway, Mapap Rapid Release Gelcaps, Mapap Rapid Tabs, Medi-Tabs, Q-Pap, Q-Pap Extra Strength, Silapap Childrens, Silapap Infants, St. Joseph Aspirin-Free, Tactinal, Tempra, Tempra Quicklets, Triaminic Fever & Pain, Triaminic Infant Drops, Tycolene, Tylenol, Tylenol Arthritis Caplet, Tylenol Arthritis Gelcap, Tylenol Caplet, Tylenol Caplet Extra Strength, Tylenol Childrens, Tylenol Cool Caplet Extra Strength, Tylenol Extra Strength, Tylenol Extra Strength Cool Caplet, Tylenol Extra Strength EZ, Tylenol Gelcap Extra Strength, Tylenol Geltab Extra Strength, Tylenol Infant's Drops, Tylenol Junior Meltaway, Tylenol Rapid Release Gelcap, Tylenol Sore Throat Daytime, Vitapap
There are many brands and forms of acetaminophen available and not all brands are listed on this leaflet.
Acetaminophen is a pain reliever and a fever reducer.
Acetaminophen is used to treat many conditions such as headache, muscle aches, arthritis, backache, toothaches, colds, and fevers.
Acetaminophen may also be used for purposes not listed in this medication guide.
There are many brands and forms of acetaminophen available and not all brands are listed on this leaflet.
Know the amount of acetaminophen in the specific product you are taking.
Ask a doctor or pharmacist if it is safe for you to take this medicine if you have liver disease or a history of alcoholism.
Ask a doctor or pharmacist if it is safe for you to take acetaminophen if you have:
a history of alcoholism.
Take exactly as directed on the label, or as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended.
Measure liquid medicine with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
The chewable tablet must be chewed thoroughly before you swallow it.
Make sure your hands are dry when handling the acetaminophen disintegrating tablet. Place the tablet on your tongue. It will begin to dissolve right away. Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.
To use the acetaminophen effervescent granules, dissolve one packet of the granules in at least 4 ounces of water. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away.
you still have a fever after 3 days of use;
you still have pain after 7 days of use (or 5 days if treating a child);
you have a skin rash, ongoing headache, or any redness or swelling; or
if your symptoms get worse, or if you have any new symptoms.
This medication can cause unusual results with certain lab tests for glucose (sugar) in the urine. Tell any doctor who treats you that you are using acetaminophen.
Since acetaminophen is taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.
nausea, upper stomach pain, itching, loss of appetite;
dark urine, clay-colored stools; or
jaundice (yellowing of the skin or eyes).
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Ask a doctor or pharmacist if it is safe for you to use acetaminophen if you are also using any of the following drugs:
an antibiotic, antifungal medicine, sulfa drug, or tuberculosis medicine;
birth control pills or hormone replacement therapy;
blood pressure medication;
cancer medications;
cholesterol-lowering medications such as Lipitor, Niaspan, Zocor, Vytorin, and others;
gout or arthritis medications (including gold injections);
HIV/AIDS medications;
medicines to treat psychiatric disorders;
an NSAID such as Advil, Aleve, Arthrotec, Cataflam, Celebrex, Indocin, Motrin, Naprosyn, Treximet, Voltaren, others; or
seizure medications.
This list is not complete and there may be other drugs that can interact with acetaminophen. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.
See also: Bromo Seltzer side effects (in more detail)
Chloramphénicol may be available in the countries listed below.
Chloramphénicol (DCF) is known as Chloramphenicol in the US.
International Drug Name Search
Glossary
| DCF | Dénomination Commune Française |
Isovue 250, 300 and 370 are NOT FOR INTRATHECAL USE.
See Indications, and Dosage and Administration sections for further details
on proper use
DIAGNOSTIC
NONIONIC RADIOPAQUE CONTRAST MEDIA
For Angiography Throughout the Cardiovascular
System, Including Cerebral and Peripheral Arteriography,
Coronary Arteriography and Ventriculography,
Pediatric Angiocardiography, Selective Visceral
Arteriography and Aortography,
Peripheral Venography (Phlebography), and
Adult and Pediatric Intravenous Excretory
Urography and Intravenous Adult and Pediatric
Contrast Enhancement of Computed Tomographic
(CECT) Head and Body Imaging
Isovue (lopamidol Injection) formulations are stable, aqueous, sterile, and nonpyrogenic solutions for intravascular administration. Each bottle is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable transfer device.
Each mL of Isovue Multipack-250 (lopamidol Injection 51%) provides 510 mg iopamidol with 1 mg tromethamine and 0. 33 mg edetate calcium disodium. The solution contains approximately 0.036 mg (0.002 mEq) sodium and 250 mg organically bound iodine per mL.
Each mL of Isovue Multipack-300 (lopamidol Injection 61%) provides 612 mg iopamidol with 1 mg tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg (0.002 mEq) sodium and 300 mg organically bound iodine per mL.
Each mL of Isovue Multipack-370 (lopamidol Injection 76%) provides 755 mg iopamidol with 1 mg tromethamine and 0.48 mg edetate calcium disodium. The solution contains approximately 0.053 mg (0.002 mEq) sodium and 370 mg organically bound iodine per mL.
The pH of Isovue contrast media has been adjusted to 6.5-7.5 with hydrochloric acid and/or sodium hydroxide. Pertinent physicochemical data are noted below. Isovue (lopamidol Injection) is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively).
| Iopamidol | |||
|---|---|---|---|
| Parameter | 51% | 61% | 76% |
| Concentration (mgl/mL) | 250 | 300 | 370 |
| Osmolality @ 37° C (mOsm/kg water) | 524 | 616 | 796 |
| Viscosity (cP) @ 37° C | 3.0 | 4.7 | 9.4 |
| @ 20° C | 5.1 | 8.8 | 20.9 |
| Specific Gravity @ 37° C | 1.281 | 1.339 | 1.405 |
lopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo-5-lactamidoisophthalamide. Structural formula:
| MW 777.09 C17H22I3N3O8 CAS-60166-93-0 Organically Bound Iodine: 49% |
Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs.
Following intravascular injection, radiopaque diagnostic agents are immediately diluted in the circulating plasma. Calculations of apparent volume of distribution at steady-state indicate that iopamidol is distributed between the circulating blood volume and other extracellular fluid; there appears to be no significant deposition of iopamidol in tissues. Uniform distribution of iopamidol in extracellular fluid is reflected by its demonstrated utility in contrast enhancement of computed tomographic imaging of the head and body following intravenous administration.
The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an open two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a slow beta phase for drug elimination). The elimination serum or plasma half-life is approximately two hours; the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation occurs.
Iopamidol is excreted mainly through the kidneys following intravascular administration. In patients with impaired renal function, the elimination half-life is prolonged dependent upon the degree of impairment. In the absence of renal dysfunction, the cumulative urinary excretion for Iopamidol, expressed as a percentage of administered intravenous dose is approximately 35 to 40 percent at 60 minutes, 80 to 90 percent at 8 hours, and 90 percent or more in the 72- to 96-hour period after administration. In normal subjects, approximately one percent or less of the administered dose appears in cumulative 72- to 96-hour fecal specimens.
Isovue may be visualized in the renal parenchyma within 30-60 seconds following rapid intravenous administration. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1 to 3 minutes, with optimum contrast occurring between 5 and 15 minutes. In patients with renal impairment, contrast visualization may be delayed.
Iopamidol displays little tendency to bind to serum or plasma proteins.
No evidence of in vivo complement activation has been found in normal subjects.
Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent following intravascular administration.
Isovue (lopamidol Injection) enhances computed tomographic brain imaging through augmentation of radiographic efficiency. The degree of enhancement of visualization of tissue density is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid injection of the dose. These levels fall rapidly within five to ten minutes. This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about ten minutes, thereafter the fall becomes exponential. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to forty minutes depending on the peak iodine levels achieved and the cell type of the lesion. This lag suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine within the lesion and outside the blood pool, although the mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool.
In CECT head imaging, Isovue (lopamidol Injection) does not accumulate in normal brain tissue due to the presence of the blood-brain barrier. The increase in x-ray absorption in normal brain is due to the presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in malignant tumors of the brain allows the accumulation of the contrast medium within the interstitial tissue of the tumor. Adjacent normal brain tissue does not contain the contrast medium.
In nonneural tissues (during computed tomography of the body), iopamidol diffuses rapidly from the vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium, and extraction of the contrast medium by interstitial tissue of tumors since no barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion between normal and abnormal tissue, quite different from that in the brain.
The pharmacokinetics of iopamidol in both normal and abnormal tissue have been shown to be variable. Contrast enhancement appears to be greatest soon after administration of the contrast medium, and following intraarterial rather than intravenous administration. Thus, greatest enhancement can be detected by a series of consecutive two- to three-second scans performed just after injection (within 30 to 90 seconds), i.e., dynamic computed tomographic imaging.
Isovue (lopamidol Injection) is indicated for angiography throughout the cardiovascular system, including cerebral and peripheral arteriography, coronary arteriography and ventriculography, pediatric angiocardiography, selective visceral arteriography and aortography, peripheral venography (phlebography), and adult and pediatric intravenous excretory urography and intravenous adult and pediatric contrast enhancement of computed tomographic (CECT) head and body imaging (see below).
Isovue may be used to refine diagnostic precision in areas of the brain which may not otherwise have been satisfactorily visualized.
Isovue may be useful to investigate the presence and extent of certain malignancies such as: gliomas including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas, ependymomas, medulloblastomas, meningiomas, neuromas, pinealomas, pituitary adenomas, craniopharyngiomas, germinomas, and metastatic lesions. The usefulness of contrast enhancement for the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been demonstrated.
In calcified lesions, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement.
The opacification of the inferior vermis following contrast media administration has resulted in false-positive diagnosis in a number of otherwise normal studies.
Isovue may be beneficial in the image enhancement of nonneoplastic lesions. Cerebral infarctions of recent onset may be better visualized with contrast enhancement, while some infarctions are obscured if contrast media are used. The use of iodinated contrast media results in contrast enhancement in about 60 percent of cerebral infarctions studied from one to four weeks from the onset of symptoms.
Sites of active infection may also be enhanced following contrast media administration.
Arteriovenous malformations and aneurysms will show contrast enhancement. For these vascular lesions, the enhancement is probably dependent on the iodine content of the circulating blood pool.
Hematomas and intraparenchymal bleeders seldom demonstrate any contrast enhancement. However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast media administration may be helpful in ruling out the possibility of associated arteriovenous malformation.
Isovue (lopamidol Injection) may be used for enhancement of computed tomographic images for detection and evaluation of lesions in the liver, pancreas, kidneys, aorta, mediastinum, abdominal cavity, pelvis and retroperitoneal space.
Enhancement of computed tomography with Isovue may be of benefit in establishing diagnoses of certain lesions in these sites with greater assurance than is possible with CT alone, and in supplying additional features of the lesions (e.g., hepatic abscess delineation prior to percutaneous drainage). In other cases, the contrast agent may allow visualization of lesions not seen with CT alone (e.g., tumor extension), or may help to define suspicious lesions seen with unenhanced CT (e.g., pancreatic cyst).
Contrast enhancement appears to be greatest within 60 to 90 seconds after bolus administration of contrast agent. Therefore, utilization of a continuous scanning technique (“dynamic CT scanning”) may improve enhancement and diagnostic assessment of tumor and other lesions such as an abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared; the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other nonvascular lesion.
Because unenhanced scanning may provide adequate diagnostic information in the individual patient, the decision to employ contrast enhancement, which may be associated with risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings.
None.
Severe Adverse Events-lnadvertent Intrathecal Administration
Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use.
These serious adverse reactions include: death, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not inadvertently administered intrathecally.
Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media.
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to guidewire and catheter manipulation, use of manifold systems and/or three way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
Caution must be exercised in patients with severely impaired renal function, those with combined renal and hepatic disease, or anuria, particularly when larger doses are administered.
Radiopaque diagnostic contrast agents are potentially hazardous in patients with multiple myeloma or other paraproteinemia, particularly in those with therapeutically resistant anuria. Myeloma occurs most commonly in persons over age 40. Although neither the contrast agent nor dehydration has been proved separately to be the cause of anuria in myelomatous patients, it has been speculated that the combination of both may be causative. The risk in myelomatous patients is not a contraindication; however, special precautions are required.
Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when injected intravenously or intraarterially.
Administration of radiopaque materials to patients known or suspected of having pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available. These patients should be monitored very closely during contrast enhanced procedures.
Reports of thyroid storm following the use of iodinated radiopaque diagnostic agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be evaluated in such patients before use of any contrast medium.
Diagnostic procedures which involve the use of any radiopaque agent should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reaction to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions may occur. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, such as congestive heart failure.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease). Patients should be well hydrated prior to and following iopamidol administration.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered (see ADVERSE REACTIONS). Patients at increased risk include those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food allergies). The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast medium, may be more accurate than pretesting in predicting potential adverse reactions. A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions but may reduce both their incidence and severity.
General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions has been reported with radiopaque media in anesthetized patients, which may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia which can reduce cardiac output and increase the duration of exposure to the contrast agent.
Even though the osmolality of iopamidol is low compared to diatrizoate or iothalamate based ionic agents of comparable iodine concentration, the potential transitory increase in the circulatory osmotic load in patients with congestive heart failure requires caution during injection. These patients should be observed for several hours following the procedure to detect delayed hemodynamic disturbances.
In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel wall, or inducing vasospasm, and or subsequent ischemic events, should be borne in mind during catheter manipulations and contrast medium injection. Test injections to ensure proper catheter placement are suggested.
Selective coronary arteriography should be performed only in selected patients and those in whom the expected benefits outweigh the procedural risk. The inherent risks of angiocardiography in patients with pulmonary hypertension must be weighed against the necessity for performing this procedure. Angiography should be avoided whenever possible in patients with homocystinuria, because of the risk of inducing thrombosis and embolism. See also Pediatric Use.
In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection or a totally obstructed venous system.
Extreme caution during injection of contrast media is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial or venous disease.
Patients receiving injectable radiopaque diagnostic agents should be instructed to:
Renal toxicity has been reported in a few patients with liver dysfunction who were given oral cholecystographic agents followed by intravascular contrast agents. Administration of intravascular agents should therefore be postponed in any patient with a known or suspected hepatic or biliary disorder who has recently received a cholecystographic contrast agent.
Other drugs should not be admixed with iopamidol.
The results of PBI and radioactive iodine uptake studies, which depend on iodine estimations, will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast media. However, thyroid function tests not depending on iodine estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected.
Any test which might be affected by contrast media should be performed prior to administration of the contrast medium.
In vitro studies with animal blood showed that many radiopaque contrast agents, including iopamidol, produced a slight depression of plasma coagulation factors including prothrombin time, partial thromboplastin time, and fibrinogen, as well as a slight tendency to cause platelet and/or red blood cell aggregation (see PRECAUTIONS-General).
Transitory changes may occur in red cell and leucocyte counts, serum calcium, serum creatinine, serum glutamic oxaloacetic transaminase (SGOT), and uric acid in urine; transient albuminuria may occur.
These findings have not been associated with clinical manifestations.
Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence of genetic toxicity was obtained in in vitro tests.
Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 2.7 and 1.4 times the maximum recommended human dose (1.48 gl/kg in a 50 kg individual), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when iopamidol is administered to a nursing woman.
Safety and effectiveness in children has been established in pediatric angiocardiography, computed tomography (head and body) and excretory urography. Pediatric patients at higher risk of experiencing adverse events during contrast medium administration may include those having asthma, a sensitivity to medication and/or allergens, cyanotic heart disease, congestive heart failure, a serum creatinine greater than 1.5 mg/dL or those less than 12 months of age.
Adverse reactions following the use of iopamidol are usually mild to moderate, self-limited, and transient.
In angiocardiography (597 patients), the adverse reactions with an estimated incidence of one percent or higher are: hot flashes 3.4%; angina pectoris 3.0%; flushing 1.8%; bradycardia 1.3%; hypotension 1.0%; hives 1.0%.
In a clinical trial with 76 pediatric patients undergoing angiocardiography, 2 adverse reactions (2.6%) both remotely attributed to the contrast media were reported. Both patients were less than 2 years of age, both had cyanotic heart disease with underlying right ventricular abnormalities and abnormal pulmonary circulation. In one patient preexisting cyanosis was transiently intensified following contrast media administration. In the second patient preexisting decreased peripheral perfusion was intensified for 24 hours following the examination. (See “PRECAUTIONS” Section for information on high risk nature of these patients.)
Intravascular injection of contrast media is frequently associated with the sensation of warmth and pain especially in peripheral arteriography and venography; pain and warmth are less frequent and less severe with Isovue (lopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium injection.
The following table of incidence of reactions is based on clinical studies with Isovue in about 2246 patients.
| Adverse Reactions | ||
|---|---|---|
| Estimated Overall Incidence | ||
| System | > 1% | ≤ 1% |
| Cardiovascular | none | tachycardia hypotension hypertension myocardial ischemia circulatory collapse S-T segment depression bigeminy extrasystoles ventricular fibrillation angina pectoris bradycardia transient ischemic attack thrombophlebitis |
| Nervous | pain (2.8%) burning sensation (1.4%) | vasovagal reaction tingling in arms grimace faintness |
| Digestive | nausea (1.2%) | vomiting anorexia |
| Respiratory | none | throat constriction dyspnea pulmonary edema |
| Skin and Appendages | none | rash urticaria pruritus flushing |
| Body as a Whole | hot flashes (1.5%) | headache fever chills excessive sweating back spasm |
| Special Senses | warmth (1.1%) | taste alterations nasal congestion visual disturbances |
| Urogenital | none | urinary retention |
Regardless of the contrast agent employed, the overall estimated incidence of serious adverse reactions is higher with coronary arteriography than with other procedures. Cardiac decompensation, serious arrhythmias, or myocardial ischemia or infarction have been reported with Isovue and may occur during coronary arteriography and left ventriculography.
Following coronary and ventricular injections, certain electrocardiographic changes (increased QTc, increased R-R, T-wave amplitude) and certain hemodynamic changes (decreased systolic pressure) occurred less frequently with Isovue (lopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium injection; increased LVEDP occurred less frequently after ventricular iopamidol injections.
In aortography, the risks of procedures also include injury to the aorta and neighboring organs, pleural puncture, renal damage including infarction and acute tabular necrosis with oliguria and anuria, accidental selective filling of the right renal artery during the translumbar procedure in the presence of preexisting renal disease, retroperitoneal hemorrhage from the translumbar approach, and spinal cord injury and pathology associated with the syndrome of transverse myelitis.
The following adverse reactions have been reported for lopamidol: Cardiovascular: arrhythmia, arterial spasms, flushing, vasodilation, chest pain, cardiopulmonary arrest; Nervous: confusion, paresthesia, dizziness, temporary cortical blindness, temporary amnesia, convulsions, paralysis, coma; Respiratory: increased cough, sneezing, asthma, apnea, laryngeal edema, chest tightness, rhinitis; Skin and Appendages: injection site pain usually due to extravasation and/or erythematous swelling, pallor, periorbital edema, facial edema; Urogenital: pain, hematuria; Special Senses: watery itchy eyes, lacrimation, conjunctivitis; Musculoskeletal: muscle spasm, involuntary leg movement; Body as a whole: tremors, malaise, anaphylactoid reaction (characterized by cardiovascular, respiratory and cutaneous symptoms), pain; Digestive: severe retching and choking, abdominal cramps. Some of these may occur as a consequence of the procedure. Other reactions may also occur with the use of any contrast agent as a consequence of the procedural hazard; these include hemorrhage or pseudoaneurysms at the puncture site, brachial plexus palsy following axillary artery injections, chest pain, myocardial infarction, and transient changes in hepatorenal chemistry tests. Arterial thrombosis, displacement of arterial plaques, venous thrombosis, dissection of the coronary vessels and transient sinus arrest are rare complications.
Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the listing below) are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of other water-soluble intravascularly administered contrast agents are mild to moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Reported incidences of death from the administration of other iodinated contrast media range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.
Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. Experience with iopamidol suggests there is much less discomfort (e.g. pain and/or warmth) with peripheral arteriography. Fewer changes are noted in ventricular function after ventriculography and coronary arteriography.
Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of drug injected, the speed of injection, the mode of injection, and the radiographic procedure.
Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.
The reported incidence of adverse reactions to contrast media in patients with a history of allergy is twice that for the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations. Most adverse reactions to intravascular contrast agents appear within one to three minutes after the start of injection, but delayed reactions may occur.
In addition to the adverse drug reactions reported for iopamidol, the following additional adverse reactions have been reported with the use of other intravascular contrast agents and are possible with the use of any water-soluble iodinated contrast agent:
Cardiovascular: cerebral hematomas, petechiae; Hematologic: neutropenia; Skin and Appendages: skin necrosis; Urogenital: osmotic nephrosis of proximal tubular cells, renal failure; Special Senses: conjunctival chemosis with infection.
Treatment of an overdose of an injectable radiopaque contrast medium is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
It is desirable that solutions of radiopaque diagnostic agents for intravascular use be at body temperature when injected. Discard the container if crystallization of the medium has occurred.
The transferring of Isovue from Isovue Multipack should be performed in a suitable work area, such as a laminar flow hood, utilizing aseptic technique. The container closure may be penetrated only one time, utilizing a suitable transfer device
Patients should be well hydrated prior to and following Isovue (lopamidol Injection) administration.
As with all radiopaque contrast agents, only the lowest dose of Isovue necessary to obtain adequate visualization should be used. A lower dose reduces the possibility of an adverse reaction. Most procedures do not require use of either a maximum dose or the highest available concentration of Isovue; the combination of dose and Isovue concentration to be used should be carefully individualized, and factors such as age, body size, size of the vessel and its blood flow rate, anticipated pathology and degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed should be considered.
Isovue-300 (lopamidol Injection, 300 mgl/mL) should be used. The usual individual injection by carotid puncture or transfemoral catheterization is 8 to 12 mL, with total multiple doses ranging to 90 mL.
Isovue-300 usually provides adequate visualization. For injection into the femoral artery or subclavian artery, 5 to 40 mL may be used; for injection into the aorta for a distal runoff, 25 to 50 mL may be used. Doses up to a total of 250 mL of Isovue-300 have been administered during peripheral arteriography.
Isovue-370 (lopamidol Injection, 370 mgl/mL) should be used. Doses up to 50 mL may be required for injection into the larger vessels such as the aorta or celiac artery; doses up to 10 mL may be required for injection into the renal arteries. Often, lower doses will be sufficient. The combined total dose for multiple injections has not exceeded 225 mL.
Isovue-370 should be used. Pediatric angiocardiography may be performed by injection into a large peripheral vein or by direct catheterization of the heart.
The usual dose range for single injections is provided in the following table:
| Single Injection | |
| Usual Dose Range | |
| Age | mL |
| < 2 years | 10-15 |
| 2-9 years | 15-30 |
| 10-18 years | 20-50 |
The usual recommended dose for cumulative injections is provided in the following table:
| Cumulative Injection | |
| Usual Recommended Dose | |
| Age | mL |
| < 2 years | 40 |
| 2-4 years | 50 |
| 5-9 years | 100 |
| 10-18 years | 125 |
Isovue-370 should be used. The usual dose for selective coronary artery injections is 2 to 10 mL. The usual dose for ventriculography, or for nonselective opacification of multiple coronary arteries following injection at the aortic root is 25 to 50 mL. The total dose for combined procedures has not exceeded 200 mL. EKG monitoring is essential.
Isovue-250 Isovue-300 or Isovue-370 may be used. The usual adult dose for Isovue-250 is 50 to 100 mL, for Isovue-300 is 50 mL and for Isovue-370 is 40 mL administered by rapid intravenous injection.
Isovue-250 or Isovue-300 may be used. The dosage recommended for use in children for excretory urography is 1.2 mL/kg to 3.6 mL/kg for Isovue-250 and 1.0 mL/kg to 3.0 mL/kg for Isovue-300. It should not be necessary to exceed a total dose of 30 grams of iodine.
Isovue-250 or Isovue-300 may be used.
CECT OF THE HEAD: The suggested dose for Isovue-250 is 130 to 240 mL and for Isovue-300 is 100 to 200 mL by intravenous administration. Imaging may be performed immediately after completion of administration.
CECT OF THE BODY: The usual adult dose range for Isovue-250 is 130 to 240 mL and for Isovue-300 is 100 to 200 mL administered by rapid intravenous infusion or bolus injection. Equivalent doses of Isovue-370 based on organically bound iodine content may also be used. The total dose for either CECT procedure should not exceed 60 grams of iodine.
Isovue-250 or Isovue-300 may be used. The dosage recommended for use in children for contrast enhanced computed tomography is 1.2 mL/kg to 3.6 mL/kg for Isovue-250 and 1.0 mL/kg to 3.0 mL/kg for Isovue-300. It should not be necessary to exceed a total dose of 30 grams of iodine.
Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, no other pharmaceuticals should be admixed with contrast agents.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Iopamidol solutions should be used only if clear and within the normal colorless to pale yellow range.
The pharmacy bulk package is used as a multiple dose container with an appropriate transfer device to fill empty sterile syringes.
Isovue Multipack injection should be drawn into the syringe and administered using sterile technique. Unused portions of the drug must be discarded.
Isovue Multipack-250 (lopamidol Injection 51%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1317-41)
Isovue Multipack-300 (lopamidol Injection 61%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1315-41)
Six 500 mL Pharmacy Bulk Packages
(NDC 0270-1315-98)
Isovue Multipack-370 (lopamidol Injection 76%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1316-41)
Six 500 mL Pharmacy Bulk Packages
(NDC 0270-1316-98)
Store at 20-25° C (68-77° F). [See USP]. Protect from light.
Manufactured for
Bracco Diagnostic Inc. - Princeton, NJ 08543
by BIPSO GmbH
78224 Singen (Germany)
Revised July 2011
F1/6057988
Isovue Multipack-250: 200mL Bottles
NDC 0270-1317-41
Isovue Multipack-300: 6x 500mL bottles Box label
NDC 0270-1316-98
Isovue Multipack-370: 200mL Bottles
NDC 0270-1316-41
| Isovue 250 iopamidol injection, solution | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA020327 | 10/12/1994 | |
| Isovue 300 iopamidol injection, solution | ||||||||||||
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Robitussin PS may be available in the countries listed below.
Guaifenesin is reported as an ingredient of Robitussin PS in the following countries:
International Drug Name Search
Trandolapril 0.5mg Capsules
Each capsule contains: Trandolapril, 0.5 mg
Each capsule contains 24 mg Lactose monohydrate
Each capsule contains 1.26 mg Sunset yellow (E110)
For a full list of excipients, see section 6.1.
Capsule, hard
Light scarlet/rich yellow capsules
Mild or moderate hypertension.
Left ventricular dysfunction after acute myocardial infarction.
Trandolapril may be taken before, during or after a meal.
Adults:
Hypertension:
For adults not taking diuretics, without congestive heart failure and without renal or hepatic insufficiency, the recommended initial dosage is 0.5 mg as a single daily dose. A 0.5 mg dose will only achieve a therapeutic response in a minority of patients. Dosage should be doubled incrementally at intervals of 2 to 4 weeks, based on patient response, up to a maximum of 4 mg as a single daily dose.
The usual maintenance dose range is 1 to 2 mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 4 mg trandolapril, combination therapy should be considered with diuretics and calcium channels blockers.
Left ventricular dysfunction after acute myocardial infarction:
After an acute myocardial infarction, treatment can be started as early as the third day once necessary treatment conditions have been attained (stable haemodynamics and management of any residual ischaemia). The initial dose must be low (see 4.4), particularly if the patient exhibits normal or low blood pressure at the initiation of therapy. Initial treatment should be 0.5 mg per day (24 hours). The dose may be increased progressively to a maximum of 4 mg daily as a single dose. This forced titration may be temporarily suspended, for example in the event of symptomatic hypotension.
Treatment should be started in hospital under strict surveillance, particularly of blood pressure (see 4.4).
In the event of hypotension, all concurrent hypotensive treatments (for example vasodilators such as nitrates, diuretics) must be assessed carefully and if possible, their dose reduced. The dose of trandolapril should be reduced only if these precautions are insufficient or cannot be effected.
In the event of prior diuretic treatment, special precautions must be taken:
It is recommended either to discontinue the diuretic treatment at least 72 hours before the trandolapril treatment is begun and/or start with 0.5 mg daily. In that case the dose must be adjusted in accordance with the patient's response. If the diuretic treatment must necessarily continue, medical supervision is necessary.
Prior diuretic treatment
In patients who are at risk from a stimulated renin-angiotensin system (e.g. patients with water and sodium depletion), the diuretic should be discontinued 2-3 days before beginning therapy with 0.5mg trandolapril to reduce the likelihood of symptomatic hypotension. The diuretic may be resumed later if required.
Cardiac failure
In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients, therapy should be started at a dose of 0.5 mg trandolapril once daily under close medical supervision in hospital.
Impaired renal function:
At a creatinine clearance of 0.2 – 0.5 ml/s (10-30 ml/min), treatment should be initiated with a daily dose of 0.5 mg. If required, the dose can be increased to 1 mg daily as a single dose. At a creatinine clearance below 0.2 ml/s (10 ml/min) and for patients in haemodialysis the dose is 0.5 mg daily as a single dose. For these patients regular supervision of serum potassium and serum creatinine is necessary.
Renovascular hypertension
Initial treatment should be 0.5mg daily. The dose should be adjusted according to the blood pressure response.
Dosage adjustment in hepatic impairment:
In patients with severely impaired liver function, a decrease in the metabolic clearance of the parent compound, trandolapril and the active metabolite trandolaprilat results in a large increase in plasma trandolapril levels and to a lesser extent, an increase in trandolaprilat levels. Treatment with trandolapril should therefore be initiated at a dose of 0.5 mg once daily under close medical supervision (see 4.4 and 5.2).
Children:
The medicinal product should not be given to children, as experience with treatment of children is insufficient.
The elderly:
Normally no dose reduction is needed. Pharmacokinetic studies of hypertensive patients over 65 who have normal kidney function for their age indicate that dose adjustment is not necessary. As some elderly patients may, however, be especially sensitive to ACE inhibitors, it is recommended initially to use low doses and to monitor the blood pressure response and the kidney function.
Caution must be exercised in elderly patients with concurrent diuretic treatment, congestive heart failure or renal or hepatic insufficiency. The dose should be adjusted according to the blood pressure response.
• Known hypersensitivity to trandolapril, other ACE inhibitors or any of the excipients.
• History of angioneurotic oedema (for example Quincke's oedema) associated with prior administration of an ACE inhibitor.
• Hereditary or idiopathic angioneurotic oedema.
• Second and third trimester of pregnancy (see section 4.4 and 4.6).
Risk of hypotension and/or renal insufficiency
In patients with uncomplicated hypertension, symptomatic hypotension has been observed in rare cases after the first dose or after an increased dose. Marked activation of the renin-angiotensin-aldosterone system occurs under certain conditions, especially in the event of severe fluid and sodium depletion (low salt diet, prolonged diuretic treatment, dialysis, diarrhoea or vomiting), renal artery stenosis, heart failure and cirrhosis of the liver with oedema and/or ascites. The ACE inhibitor's suppression of the renin-angiotensin-aldosterone system may cause severe arterial hypotension and/or functional renal insufficiency, especially at the first dosage, when the dose is increased and during the first two weeks of treatment. Severe hypotension may lead to fainting and/or ischaemic lesions in organs with arterial disorders (for example acute myocardial infarction, cerebrovascular infarction).
In such risk patients, including those with angina pectoris or cerebrovascular disorders, trandolapril treatment should be initiated under close medical supervision in low doses, with careful dose adjustment. In the event of prior diuretic treatment it is recommended to discontinue the diuretic treatment at least 72 hours before the trandolapril treatment is initiated and begin with 0.5 mg daily (see section 4.5).
Fluid and salt depletion should be remedied before initiating trandolapril treatment.
If the patient develops arterial hypotension or renal insufficiency during treatment, dose reduction or suspension of the treatment with trandolapril and/or diuretics may be necessary.
A case of arterial hypotension occurring after the initial dose does not exclude subsequent treatment with trandolapril provided the dose is adjusted carefully.
If symptomatic hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline. Intravenous atropine may be necessary if there is associated bradycardia.
Patients with renovascular hypertension
Treatment of renovascular hypertension is carried out by revascularisation.
However, ACE inhibitors may be of use until revascularisation can be effected, or if such a procedure is not to be carried out. The risk of severe arterial hypotension and renal insufficiency is increased when patients with prior unilateral or bilateral renal artery stenosis are treated with an ACE inhibitor. Diuretics may further increase the risk. Loss of renal function may occur with only small changes in the serum creatinine, even in patients with unilateral renal artery stenosis. For these patients treatment should be initiated in the hospital under close medical supervision with low doses and careful dose adjustment. Diuretic treatment should be discontinued, and renal function and serum potassium monitored during the early weeks of treatment.
Assessment of renal function
Evaluation of the patient should include assessment of renal function prior to initiation of therapy and during treatment. Proteinuria may occur if renal impairment is present prior to therapy or relatively high doses are used.
Patients with renal insufficiency
In the event of renal insufficiency the dose must be reduced if the creatinine clearance is
In patients with renal insufficiency, congestive heart failure or unilateral or bilateral renal artery stenosis, in the single kidney as well as after renal transplantation, there is a risk of impairment of renal function. If recognised early, such impairment of renal function is reversible upon discontinuation of therapy.
Kidney transplantation
There is no experience regarding the administration of trandolapril in patients with a recent kidney transplantation. Treatment with trandolapril is therefore not recommended.
Patients with impaired liver function
As trandolapril is a prodrug metabolised to its active form in the liver, particular caution and close monitoring should be applied to patients with impaired liver function.
Hepatic failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Angio oedema
Cases of oedema in the face, lips, tongue, glottis and/or larynx as well as the extremities have been reported in patients treated with an ACE inhibitor, including trandolapril. Angio oedema may occur particularly during the early weeks of treatment. Seldom does it develop only after prolonged treatment with an ACE inhibitor.
In such cases the trandolapril treatment should be discontinued, and the patient monitored until the oedema disappears. When the oedema is localised to include only the face, it generally disappears without treatment, although antihistamines have been useful in relieving symptoms.
The combination of facial and larynx oedema may be life-threatening. Swelling of the tongue, glottis or larynx may cause respiratory obstruction. Subcutaneous adrenaline 0.1% (0.3-0.5 ml) must be given rapidly and other therapeutic measures taken as appropriate.
After such a reaction treatment with an ACE inhibitor must not be resumed. Patients with prior Quincke's oedema not occurring in connection with ACE inhibitor treatment run a greater risk of a new Quincke's oedema if they are treated with an ACE inhibitor (see section 4.3).
It has been shown that ACE inhibitors more frequently cause angio oedema in Negroid than in non-Negroid patients.
Intestinal angio edema has been reported very rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angio edema and C-1 esterase levels were normal. The angio edema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angio edema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (see 4.8).
Ethnic differences
As is the case with other ACE inhibitors, trandolapril may be less effective lowering blood pressure in Negroid than in non-Negroid patients. This may possibly be due to a higher incidence of low renin conditions in hypertensive Negroid patients.
Cough
During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation. If treatment with an ACE inhibitor is considered essential, a resumption of treatment may be considered.
ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Trandolapril. Risk factors for the development of hyperkalemia include renal insufficiency, worsening of the renal condition, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g., heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal arrhythmias. If concomitant use of trandolapril and any of the abovementioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium. (See 4.5).
Surgery/ anaesthesia
In patient undergoing major surgery or during anaesthesia with potentially hypotensive agents, ACE inhibitors may induce a possibly severe arterial hypotension, which can be corrected with plasma expanders. If it is not possible to discontinue treatment with the ACE inhibitor, volume therapy should be given with care.
Aortic stenosis/hypertrophic cardiomyopathy
ACE inhibitors should be used with great caution in patients with aortic stenosis or obstructed outflow from the left ventricle.
Neutropenia/ agranulocytosis
In very rare cases neutropenia /agranulocytosis have been observed after treatment with ACE inhibitors administered in high doses and/or to patients with renal insufficiency, particularly associated with connective tissue diseases (for example lupus erythematosus disseminatus and scleroderma) as well as immunosuppressive therapy with agents having a potential risk of leucopoenia. Neutropenia is reversible after discontinuation of the ACE inhibitor. The best prevention is to keep carefully to the recommended dose. If treatment with an ACE inhibitor is deemed necessary in such risk patients, the risk/benefit ratio must be considered carefully. Regular monitoring of the white blood vessels and protein in the urine must be considered in patients with collagen vascular diseases (for example lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy, particularly with corticosteroids and antimetabolites, or treatment with allopurinol or procainamide.
Proteinuria
Proteinuria may occur particularly in patients with existing renal function impairment or relatively high doses of ACE inhibitors. Trandolapril should only be administered after critical evaluation of the risk/benefit of treatment of patients with clinically relevant proteinuria (more than 1 g/day).
Anaphylactoid reactions during hymenoptera desensitization
Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitization.
Anaphylactoid reactions during LDL apheresis
Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.
Haemodialysis patients
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69®) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Diabetic patients
In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Interactions
This medicinal product IS GENERALLY NOT RECOMMENDED in combination with potassium-sparing diuretics, potassium salts and lithium (see section 4.5).
Contains lactose
Patients with hereditary galactose intolerance, a particular form of hereditary lactase deficiency (Lapp Lactase deficiency), or glucose/galactose malabsorption should not take this medicine.
Not recommended combinations (see section 4.4)
Potassium or potassium-sparing diuretics: Amiloride, potassium canrenoate, spironolactone, triamterene, potassium (salts):
Concurrent administration of potassium or potassium-sparing diuretics increases the risk of hyperkalaemia, particularly in renal failure. Should this combination be considered necessary, frequent monitoring of serum potassium is essential.
Lithium:
Increased lithium concentration, potentially to toxic levels (decreased renal lithium excretion).
Use of Trandolapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.
Combination requiring a precaution for use
Thiazidics and loop diuretics:
Patients in diuretic treatment, especially patients who have recently begun treatment or patients with volume and/or salt depletion, may develop a severe fall in blood pressure and/or pre-renal failure after initial treatment with an ACE inhibitor. The risk of hypotensive episodes can be reduced by discontinuing the diuretics, by increasing salt intake beforehand and by starting treatment with lower initial doses of ACE inhibitor. Further dose increase should be made with caution. Trandolapril may attenuate the potassium loss caused by thiazidics and loop diuretics.
Antihypertensive agents:
The combination of trandolapril and other antihypertensive agents may potentiate the antihypertensive response to ACE inhibitors.
Antipsychotic agents:
Postural hypotension may occur if administered concurrently.
Allopurinol, procaiamide, cytostatic or immunosuppressive agents, systemic corticosteroids:
If used concomitantly with ACE inhibitors, they may increase the risk of leucopoenia.
Non-steroid anti-inflammatory medicinal products:
When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (ie acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Antidiabetics (insulin, hypoglycaemic sulphonamides):
Although clinical studies do not observe an increased risk of hypoglycaemia in diabetic patients treated with insulin or oral antidiabetics concurrently with an ACE inhibitor, cases of hypoglycaemia have been reported in such patients. Therefore, blood glucose should be closely monitored in diabetics, particularly when starting or increasing the dose of an ACE inhibitor.
Antacids:
Concurrent administration may lead to reduced absorption of ACE inhibitors. Therefore, at least two hours should elapse between administration of trandolapril and antacids.
Use of high-flux polyacrylonitrile membranes in haemodialysis:
Anaphylactoid reactions to high-flux polyacrylonitrile membranes used in haemodialysis have been reported in patients treated with ACE inhibitors. As with other antihypertensives of this chemical class, this combination should be avoided when prescribing ACE inhibitors to renal dialysis patients.
Absence of interactions with other medicinal products:
In studies on healthy volunteers, pharmacokinetic interactions were not observed when trandolapril was combined with digoxin, furosemide, nifedipin, glibenclamide, propranolol or cimetidin. The anticoagulant properties of warfarin were not affected after concurrent administration of trandolapril.
Clinical interactions were not observed in patients with left ventricular dysfunction after acute myocardial infarction when trandolapril was administered concurrently with thrombolytics, acetylsalicylic acid, beta blockers, calcium antagonists, nitrates, anticoagulants, diuretics or digoxin.
Pregnancy
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Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see also section 4.3 and 4.4).
Lactation
Because no information is available regarding the use of Trandolapril during breastfeeding, Trandolapril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Due to individual differences in reaction to an ACE inhibitor, the ability to drive or operate machinery may be reduced.
Particularly at the start of treatment, after increases in dose or during concurrent use of alcohol, trandolapril may affect the ability to drive or to operate machinery in a lesser or a moderate degree.
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Undesirable effects reported for ACE inhibitors as a class (frequency not given):
Investigations:
Decreased haemoglobin and haematocrit.
Cardiac disorders:
Angina pectoris, myocardial infarction, AV block, bradycardia, cardiac arrest, tachycardia.
Blood and lymphatic system disorders:
Pancytopoenia.
Respirathoratory, thoracic and mediastinal disorders:
Sinusitis, rhinitis, glossitis, bronchospasm
Gastrointestinal disorders:
Ileus
Renal and urinary disorders:
Elevated serum bilirubin, haemolytic anaemia with a congenital deficiency concerning G-6 PDH (glucose-6-phosphate dehydrogenase).
Skin and subcutaneous tissue disorders:
Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like efflorescences and alopecia.
Vascular disorders:
Cerebral haemorrhage, transient ischaemia.
Hepatobiliary disorders:
Cholestatic jaundice, hepatitis
Symptoms:
The highest doses used in clinical studies are 32 mg (single doses given to healthy volunteers) and 16 mg (repeated doses to hypertensive patients), respectively.
Symptoms of overdose are severe hypotension, shock, stupor, bradycardia, electrolyte disturbance and renal failure.
Treatment:
After ingestion of an overdose the patient should be monitored closely, preferably in an intensive care unit. Serum electrolytes and serum creatinine are to be measured frequently. Therapeutic procedures depend on the severity of the symptoms. Consideration should be given to emptying the stomach contents if the ingestion is recent. In the event of symptomatic hypotension the patient is placed in the shock position. Severe hypotension can be corrected by physiological salt solution or other forms of plasma expansion. Treatment with angiotensin II may be considered in a referral centre.
Trandolaprilat can be eliminated from the body by haemodialysis.
Pharmacotherapeutic group: ACE Inhibitors, plain - ATC code: C 09 AA10
Trandolapril is a prodrug, which is rapidly, non-specifically hydrolysed to its potent, long-acting active metabolite, trandolaprilat (other metabolites are inactive) and acts as an orally-active angiotensin converting enzyme inhibitor (ACE inhibitor) without a sulphydryl group. In addition to inhibition of plasma ACE, trandolapril has been experimentally shown to inhibit tissue ACE (particularly vascular, cardial and adrenal). The clinical relevance of tissue ACE inhibition has not been established in humans.
The angiotensin converting enzyme is a peptidyl-dipeptidase, which catalyses the transformation of angiotensin I to the vasoconstrictive angiotensin II and promotes metabolism of bradykinin to inactive fragments.
Small doses of trandolapril induce a potent ACE inhibition, which reduces the angiotensin II production, decreases the aldosterone secretion and increases plasma renin activity by inhibition of the negative feedback regulation.
Trandolapril thus modulates the renin/angiotensin/aldosterone system, which plays a significant role in regulating blood volume and blood pressure.
Inhibition of bradykinin degradation, prostaglandin release and reduced activity in the sympathetic nervous system are other mechanisms of action which may be of importance for ACE inhibitors' vasodilatory activity.
The properties of trandolapril may explain the results obtained in the regression of cardiac hypertrophy with improvement of diastolic function, and improvement of arterial compliance in humans. In addition, a decrease in vascular hypertrophy has been shown in animals.
The drop in peripheral resistance induced by trandolapril is accompanied neither by fluid and salt retention nor by tachycardia.
In hypertensive patients trandolapril reduces the systolic and diastolic blood pressure. Trandolapril has an antihypertensive activity which is independent of the plasma renin level.
In humans the antihypertensive effect of trandolapril is evident about 1 hour after administration, and persists for at least 24 hours, enabling dosage once daily. Trandolapril does not affect the circadian (24-hour) rhythm of the blood pressure.
The antihypertensive effect is maintained during long term treatment without the development of tolerance. There is no rebound effect after discontinuation of treatment. Trandolapril treatment is accompanied by a higher score in evaluating the quality of life.
Combination with a diuretic or a calcium antagonist potentiates the antihypertensive effect of trandolapril.
A multi-centre, placebo-controlled clinical study was performed on patients with left ventricular dysfunction after acute myocardial infarction. A total of 1749 patients were randomised to receive either placebo or trandolapril from the third day after acute myocardial infarction and were followed for at least 24 months.
Trandolapril treatment resulted in 22 % reduction in total mortality, 25 % reduction of cardio-vascular mortality, 24 % reduction of risk of sudden death, 29 % reduction in the incidence of severe or resistant cardiac insufficiency and 14 % reduction of recurrent myocardial infarction.
Compared with placebo the patients in trandolapril treatment had significantly fewer clinical symptoms of cardiac insufficiency, peripheral oedema, dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea and fatigue.
Absorption:
Trandolapril is absorbed rapidly after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption. About 36 % of the absorbed amount is converted to trandolaprilat. The bioavailability of trandolaprilat is about 13 % following oral administration of trandolapril.
Distribution - Biotransformation - Excretion:
Peak plasma concentration for trandolapril is achieved about 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.
Trandolapril is hydrolysed to the active metabolite trandolaprilat, a specific ACE (angiotensin converting enzyme) inhibitor. The amount of trandolaprilat formed is not modified by food consumption. Peak plasma concentration for trandolaprilat is reached 4 to 6 hours after administration.
In the plasma, trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to ACE. Trandolaprilat is also non-saturably bound to albumin.
After repeated administration of single daily doses of trandolaprilat, steady state was reached on average in four days, both in healthy volunteers and in young or elderly hypertensives as well as patients with cardiac insufficiency. The effective half-life of trandolaprilat accumulation is between 16 and 24 hours.
Excretion of non-metabolised trandolaprilat in the urine accounts for 10-15 % of the dose administered. After oral administration of the labelled product, 33% of the radioactivity is found in the urine and 66% in the faeces.
Renal insufficiency:
The renal clearance of trandolaprilat (about 70 ml/min) is proportional to the creatinine clearance. The plasma concentrations of trandolaprilat are significantly higher in patients with a creatinine clearance of
After repeated dosing in patients with chronic renal failure, steady state is also reached in about four days, whatever the degree of renal failure.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. These include anaemia and gastric irritation and ulceration.
Studies of reproductive toxicity found affected renal development in rat young with increased incidence of renal pelvis dilatation after doses of at least 10 mg/kg/day, but the normal development of the offspring was not affected.
Trandolapril was not mutagenic or carcinogenic.
Dimeticone
Cellulose, microcrystalline
Lactose monohydrate
Starch, pregelatinised maize
Silica, colloidal anhydrous
Magnesium stearate
Capsules shell
Gelatin
Titanium dioxide (E171)
Erythrosine (E127)
Sunset yellow (E110)
Quinoline yellow (E104)
Not applicable.
5 years
Store below 25°C
Store in the original package
Blister (PVC/PE/PVDC/Al)
0.5 mg, 1 mg, 2 mg and 4 mg:
14, 20, 28, 30, 50, 56, 84, 90 and 100 capsules.
Not all pack sizes may be marketed.
No special requirements
Actavis Group PTC ehf
Reykjavíkurvegi 76-78
IS-220 Hafnarfjörður
Iceland
PL 30306/0001
12.03.08
27/08/10
(IF APPLICABLE)
(IF APPLICABLE)
